Aminoglycoside antibiotics, such as gentamicins, kanamycins, streptomycins and tobramycins, are generally utilized as broad spectrum antimicrobials effective against, for example, gram-positive, gram-negative and acid-fast bacteria. Nonetheless, the aminoglycosides are used primarily to treat infections caused by gram-negative bacteria and, for instance, in combination with penicillins for the synergistic effects. As implied by the generic name for the family, all the aminoglycoside antibiotics contain aminosugars in glycosidic linkage. Further, the aminoglycosides are characterized as polycations, and their polarity is responsible for the pharmocokinetic properties shared by all members of the family.
The aminoglycoside antibiotics, however, are often associated with undesired side-effects such as nephrotoxicity and ototoxicity. The seriousness of these toxicities is a major limitation to their usefulness, and, unfortunately, the same spectrum of toxicity is shared by all members of the family. It has been estimated, as of March 1983, that about 3.2 million or more people receive aminoglycoside therapy each year. Of those people receiving treatment, from about 2% to about 10% suffer clinical nephrotoxicity, as defined as an increase in serum creatinine of at least 0.4 mg/dl or onset acute renal failure. Thusly, the mechanisms and predisposing factors of aminoglycoside nephrotoxicity is critical in any attempt to minimize risk of therapy with these pharmaceuticals. Francke E. et al: Nephrotoxicity of Aminoglycosides. Infections in Surgery. Pages 204-214 (March 1983). In the past, it has been found that the toxic properties of many of the aminoglycoside antibiotics can be altered or reduced by structural modifications as described in U.S. Pat. No. 4,393,051 issued July 12, 1983 to P. Stadler et al.; U.S. Pat. No. 4,273,923, issued June 16, 1981 to K. Igarashi et al.; U.S. Pat. No. 4,248,865, issued Feb. 3, 1981 to K. Igarashi et al.; U.S. Pat. No. 4,201,774 issued May 6, 1982 to K. Igarashi et al.; U.S. Pat. No. 4,200,628, issued Apr. 29, 1980 to K. Igarashi et al.; and U.S. Pat. No. 4,199,570 issued Apr. 22, 1980 to K. Igarashi et al. In particular, it has been disclosed in U.S. Pat. Nos. 4,427,662 and 4,423,210, issued Jan. 24, 1984 to J. S. Tadanier et al. and Dec. 27, 1983 to J. B. McAlpine et al., respectively, that certain chemical modifications in the fortimicin, kanamycin and gentamicin family of aminoglycoside antibiotics provide structures which are less toxic than the parent antibiotics. Further, U.S. Pat. No. 4,335,114 issued June 15, 1982 to E. Voss et al. discloses derivatives of the aminoglycoside antibiotic sisomicin which avoid or reduce the undesired abovementioned toxicities.
Also, it has been found through testing in rats that dietary calcium loading reduces experimental gentamicin nephrotoxicity. More particularly, the effects of dietary calcium loading delay or attenuate gentamicin-mediated renal dysfunction and structural damage in Fischer line 344 rats. Since in vitro gentamicin uptake by rat renal cortical slices incubated in Cross and Taggart medium was reduced by calcium, it is postulated that the protection afforded with dietary calcium loading may be associated with slower renal cortical accumulation of gentamicin possibly mediated by calcium-dependent membrane or intracellular events. W. M. Bennett et al.: Reduction of the Experimental Gentamicin Nephrotoxicity in Rats by Dietary Calcium Loading. Antimicrobial Agents in Chemotherapy. 22(3): 508-512 (September 1982).
Amprolium [1-(4-amino-2-n-propyl-5-pyrimidinylethyl)2-picolinium chloride.hydrochloride], also known as amiloride, is a coccidostat presently used in veterinary medicine. It is a weak anti-metabolite of thiamine which is capable of producing thiamine deficiency in chicks, adult chickens and eggs. Administration of thiamine, however, overcomes the vitamin deficiency. Notwithstanding this shortcoming, amprolium is quite non-toxic and is allowed as a residue in eggs for human consumption when it is given to chickens. Amprolium is one of the few positively charged (cationic) compounds that is secreted by the proximal tubular system of the kidneys which has minimal biological and/or pharmacological activity. Generally, the majority of positively charged compounds are very active biologically and pharmacologically and, therefore, can only be given in small doses. An example of a positively charged compound which is well-known, very pharmacologically active and secreted by the proximal tubules is nicotine.
It is generally accepted today that positively charged (cationic) molecules induce nephrotoxicity. For instance, proteins having an increased isoelectric point, like Bence Jones proteins, are thought to cause kidney damage in part by inhibition of proteolytic enzyme activity. The predisposing factors by which positively charged molecules, such as aminoglycosides and Bence Jones proteins, induce nephrotoxicity are believed to be due to their filtration through the glomerula membrane, their binding to the membranes of the proximal tubule cells and their accumulation within the proximal tubule cells of the kidney. As to aminoglycosides, it is believed that absorption occurs exclusively along the proximal tubules and Henley's Loop and that pinocytosis is the major mechanism of aminoglycoside entry into the proximal tubule cells. Once inside the proximal tubule cells, it is postulated that the pathophysiology and epidemiology associated with the nephrotoxicity of these drugs is due to their ability to disrupt lysosomal function and/or release active unhibited lysosomal enzymes. E. Francke et al.: Nephrotoxicity of Aminoglycosides. Infections in Surgery. Pages 205-214 (March 1983).
In other words, positively charged molecules, and especially the most popular and commonly used aminoglycoside antibiotics provided hitherto invariably necessarily induce undesired nephrotoxic effects. Consequently, there are strong medical needs for developing a pharmaceutical substance and/or a course of therapy that will reduce the nephrotoxicity presently associated with positively charged molecules, and particularly the commonly used aminoglycosides.